Pre-existing tolerance shapes the outcome of mucosal allergen sensitization in a murine model of asthma.

Recent published studies have highlighted the complexity of the immune response to allergens, and the various asthma phenotypes that arise as a result. Although the interplay of regulatory and effector immune cells responding to allergen would seem to dictate the nature of the asthmatic response, little is known regarding how tolerance versus reactivity to allergen occurs in the lung. The vast majority of mouse models study allergen encounter in naive animals, and therefore exclude the possibility that previous encounters with allergen may influence future sensitization. To address this, we studied sensitization to the model allergen OVA in mice in the context of pre-existing tolerance to OVA. Allergen sensitization by either systemic administration of OVA with aluminum hydroxide or mucosal administration of OVA with low-dose LPS was suppressed in tolerized animals. However, higher doses of LPS induced a mixed Th2 and Th17 response to OVA in both naive and tolerized mice. Of interest, tolerized mice had more pronounced Th17-type inflammation than did naive mice receiving the same sensitization, suggesting pre-existing tolerance altered the inflammatory phenotype. These data show that a pre-existing tolerogenic immune response to allergen can affect subsequent sensitization in the lung. These findings have potential significance for understanding late-onset disease in individuals with severe asthma.